Pharmaceuticals

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Open AccessReview

Antimicrobial Peptides in 2014

by Guangshun Wang, Biswajit Mishra, Kyle Lau, Tamara Lushnikova, Radha Golla and Xiuqing Wang

Pharmaceuticals 2015, 8(1), 123-150; https://doi.org/10.3390/ph8010123 - 23 Mar 2015

Cited by 168 | Viewed by 25002

This article highlights new members, novel mechanisms of action, new functions, and interesting applications of antimicrobial peptides reported in 2014. As of December 2014, over 100 new peptides were registered into the Antimicrobial Peptide Database, increasing the total number of entries to 2493. [...] Read more.

This article highlights new members, novel mechanisms of action, new functions, and interesting applications of antimicrobial peptides reported in 2014. As of December 2014, over 100 new peptides were registered into the Antimicrobial Peptide Database, increasing the total number of entries to 2493. Unique antimicrobial peptides have been identified from marine bacteria, fungi, and plants. Environmental conditions clearly influence peptide activity or function. Human α-defensin HD-6 is only antimicrobial under reduced conditions. The pH-dependent oligomerization of human cathelicidin LL-37 is linked to double-stranded RNA delivery to endosomes, where the acidic pH triggers the dissociation of the peptide aggregate to release its cargo. Proline-rich peptides, previously known to bind to heat shock proteins, are shown to inhibit protein synthesis. A model antimicrobial peptide is demonstrated to have multiple hits on bacteria, including surface protein delocalization. While cell surface modification to decrease cationic peptide binding is a recognized resistance mechanism for pathogenic bacteria, it is also used as a survival strategy for commensal bacteria. The year 2014 also witnessed continued efforts in exploiting potential applications of antimicrobial peptides. We highlight 3D structure-based design of peptide antimicrobials and vaccines, surface coating, delivery systems, and microbial detection devices involving antimicrobial peptides. The 2014 results also support that combination therapy is preferred over monotherapy in treating biofilms. Full article

(This article belongs to the Special Issue Choices of the Journal)

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Open AccessArticle

A Retrospective Study of the Impact of 21-Gene Recurrence Score Assay on Treatment Choice in Node Positive Micrometastatic Breast Cancer

by Thomas G. Frazier, Kevin R. Fox, J. Stanley Smith, Christine Laronga, Anita McSwain, Devchand Paul, Michael Schultz, Joseph Stilwill, Christine Teal, Tracey Weisberg, Judith F. Vacchino, Amy P. Sing, Dasha Cherepanov, Wendy Hsiao, Eunice Chang and Michael S. Broder

Pharmaceuticals 2015, 8(1), 107-122; https://doi.org/10.3390/ph8010107 - 17 Mar 2015

Cited by 4 | Viewed by 6736

Abstract

To assess clinical utility of the 21-gene assay (Oncotype DX^® Recurrence Score^®), we determined whether women with HER2(−)/ER+ pN1mi breast cancer with low (<18) Recurrence Scores results are given adjuvant chemotherapy in a lower proportion than those with high [...] Read more.

To assess clinical utility of the 21-gene assay (Oncotype DX^® Recurrence Score^®), we determined whether women with HER2(−)/ER+ pN1mi breast cancer with low (<18) Recurrence Scores results are given adjuvant chemotherapy in a lower proportion than those with high scores (≥31). This was a multicenter chart review of ≥18 year old women with pN1mi breast cancer, HER2(−)/ER+ tumors, ductal/lobular/mixed histology, with the assay ordered on or after 1 January 2007. One hundred and eighty one patients had a mean age of 60.7 years; 82.9% had ECOG performance status 0; 33.7% had hypertension, 22.7% had osteoporosis, 18.8% had osteoarthritis, and 8.8% had type-2 diabetes. Mean Recurrence Score was 17.8 (range: 0–50). 48.6% had a mastectomy; 55.8% had a lumpectomy. 19.8% of low-risk group patients were recommended chemotherapy vs. 57.9% in the intermediate-risk group and 100% in the high-risk group (p < 0.001). A total of 80.2% of the low-risk group were recommended endocrine therapy alone, while 77.8% of the high-risk group were recommended both endocrine and chemotherapy (p < 0.001). The Oncotype DX Recurrence Score result provides actionable information that can be incorporated into treatment planning for women with HER2(−)/ER+ pN1mi breast cancer. The Recurrence Score result has clinical utility in treatment planning for HER2(−)/ER+ pN1mi breast cancer patients. Full article

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Open AccessReview

Hitting the Bull’s-Eye in Metastatic Cancers—NSAIDs Elevate ROS in Mitochondria, Inducing Malignant Cell Death

by Stephen John Ralph, Rhys Pritchard, Sara Rodríguez-Enríquez, Rafael Moreno-Sánchez and Raymond Keith Ralph

Pharmaceuticals 2015, 8(1), 62-106; https://doi.org/10.3390/ph8010062 - 13 Feb 2015

Cited by 42 | Viewed by 18078

Abstract

Tumor metastases that impede the function of vital organs are a major cause of cancer related mortality. Mitochondrial oxidative stress induced by hypoxia, low nutrient levels, or other stresses, such as genotoxic events, act as key drivers of the malignant changes in primary [...] Read more.

Tumor metastases that impede the function of vital organs are a major cause of cancer related mortality. Mitochondrial oxidative stress induced by hypoxia, low nutrient levels, or other stresses, such as genotoxic events, act as key drivers of the malignant changes in primary tumors to enhance their progression to metastasis. Emerging evidence now indicates that mitochondrial modifications and mutations resulting from oxidative stress, and leading to OxPhos stimulation and/or enhanced reactive oxygen species (ROS) production, are essential for promoting and sustaining the highly metastatic phenotype. Moreover, the modified mitochondria in emerging or existing metastatic cancer cells, by their irreversible differences, provide opportunities for selectively targeting their mitochondrial functions with a one-two punch. The first blow would block their anti-oxidative defense, followed by the knockout blow—promoting production of excess ROS, capitulating the terminal stage—activation of the mitochondrial permeability transition pore (mPTP), specifically killing metastatic cancer cells or their precursors. This review links a wide area of research relevant to cellular mechanisms that affect mitochondria activity as a major source of ROS production driving the pro-oxidative state in metastatic cancer cells. Each of the important aspects affecting mitochondrial function are discussed including: hypoxia, HIFs and PGC1 induced metabolic changes, increased ROS production to induce a more pro-oxidative state with reduced antioxidant defenses. It then focuses on how the mitochondria, as a major source of ROS in metastatic cancer cells driving the pro-oxidative state of malignancy enables targeting drugs affecting many of these altered processes and why the NSAIDs are an excellent example of mitochondria-targeted agents that provide a one-two knockout activating the mPTP and their efficacy as selective anticancer metastasis drugs. Full article

(This article belongs to the Special Issue Mitochondrial Target-Based Drug Discovery)

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Open AccessReview

γδ T Cell Immunotherapy—A Review

by Hirohito Kobayashi and Yoshimasa Tanaka

Pharmaceuticals 2015, 8(1), 40-61; https://doi.org/10.3390/ph8010040 - 12 Feb 2015

Cited by 55 | Viewed by 9352

Abstract

Cancer immunotherapy utilizing Vγ9Vδ2 T cells has been developed over the past decade. A large number of clinical trials have been conducted on various types of solid tumors as well as hematological malignancies. Vγ9Vδ2 T cell-based immunotherapy can be classified into two categories [...] Read more.

Cancer immunotherapy utilizing Vγ9Vδ2 T cells has been developed over the past decade. A large number of clinical trials have been conducted on various types of solid tumors as well as hematological malignancies. Vγ9Vδ2 T cell-based immunotherapy can be classified into two categories based on the methods of activation and expansion of these cells. Although the in vivo expansion of Vγ9Vδ2 T cells by phosphoantigens or nitrogen-containing bisphosphonates (N-bis) has been translated to early-phase clinical trials, in which the safety of the treatment was confirmed, problems such as activation-induced Vγ9Vδ2 T cell anergy and a decrease in the number of peripheral blood Vγ9Vδ2 T cells after infusion of these stimulants have not yet been solved. In addition, it is difficult to ex vivo expand Vγ9Vδ2 T cells from advanced cancer patients with decreased initial numbers of peripheral blood Vγ9Vδ2 T cells. In this article, we review the clinical studies and reports targeting Vγ9Vδ2 T cells and discuss the development and improvement of Vγ9Vδ2 T cell-based cancer immunotherapy. Full article

(This article belongs to the Special Issue Cell Therapy)

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Open AccessEditorial

Acknowledgement to Reviewers of Pharmaceuticals in 2014

by Pharmaceuticals Editorial Office

Pharmaceuticals 2015, 8(1), 38-39; https://doi.org/10.3390/ph8010038 - 8 Jan 2015

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Abstract

The editors of Pharmaceuticals would like to express their sincere gratitude to the following reviewers for assessing manuscripts in 2014:[...] Full article

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Open AccessArticle

Etomidate and Ketamine: Residual Motor and Adrenal Dysfunction that Persist beyond Recovery from Loss of Righting Reflex in Rats

by Daniel Diaz-Gil, Noomi Mueller, Ingrid Moreno-Duarte, Hsin Lin, Cenk Ayata, Cristina Cusin, Joseph F. Cotten and Matthias Eikermann

Pharmaceuticals 2015, 8(1), 21-37; https://doi.org/10.3390/ph8010021 - 29 Dec 2014

Cited by 8 | Viewed by 8878

Abstract

We tested the hypothesis that etomidate and ketamine produce residual effects that modify functional mobility (measured by the balance beam test) and adrenal function (adrenocorticotropic hormone (ACTH) stimulation) immediately following recovery from loss of righting reflex in rats. Intravenous etomidate or ketamine was [...] Read more.

We tested the hypothesis that etomidate and ketamine produce residual effects that modify functional mobility (measured by the balance beam test) and adrenal function (adrenocorticotropic hormone (ACTH) stimulation) immediately following recovery from loss of righting reflex in rats. Intravenous etomidate or ketamine was administered in a randomized, crossover fashion (2 or 4 mg/kg and 20 or 40 mg/kg, respectively) on eight consecutive days. Following recovery of righting reflex, animals were assessed for residual effects on functional mobility on the balance beam, motor behavior in the open field and adrenal function through ACTH stimulation. We evaluated the consequences of the effects of the anesthetic agent-induced motor behavior on functional mobility. On the balance beam, etomidate-treated rats maintained their grip longer than ketamine-treated rats, indicating greater balance abilities (mean ± SD, 21.5 ± 25.1 s vs. 3.0 ± 4.3 s respectively, p < 0.021). In the open field test, both dosages of etomidate and ketamine had opposite effects on travel behavior, showing ketamine-induced hyperlocomotion and etomidate-induced hypolocomotion. There was a significant interaction between anesthetic agent and motor behavior effects for functional mobility effects (p < 0.001). Corticosterone levels were lower after both 40 mg/kg ketamine and 4 mg/kg etomidate anesthesia compared to placebo, an effect stronger with etomidate than ketamine (p < 0.001). Following recovery from anesthesia, etomidate and ketamine have substantial side effects. Ketamine-induced hyperlocomotion with 20 and 40 mg/kg has stronger effects on functional mobility than etomidate-induced hypolocomotion with 2 and 4 mg/kg. Etomidate (4 mg/kg) has stronger adrenal suppression effects than ketamine (40 mg/kg). Full article

(This article belongs to the Special Issue Anaesthetics)

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Open AccessReview

Clinical Use of Proteasome Inhibitors in the Treatment of Multiple Myeloma

by Noah M. Merin and Kevin R. Kelly

Pharmaceuticals 2015, 8(1), 1-20; https://doi.org/10.3390/ph8010001 - 24 Dec 2014

Cited by 71 | Viewed by 9159

Abstract

Multiple myeloma (MM) is an incurable hematological malignancy characterized by the clonal proliferation of neoplastic plasma cells. The use of proteasome inhibitors in the treatment of MM has led to significant improvements in outcomes. This article reviews data on the use of the [...] Read more.

Multiple myeloma (MM) is an incurable hematological malignancy characterized by the clonal proliferation of neoplastic plasma cells. The use of proteasome inhibitors in the treatment of MM has led to significant improvements in outcomes. This article reviews data on the use of the two approved proteasome inhibitors (bortezomib and carlfilzomib), as well as newer agents under development. Emphasis is placed on the clinical use of proteasome inhibitors, including management of side effects and combination with other agents. Full article

(This article belongs to the Special Issue New Agents Targeting Regulators of Protein Homeostasis for Cancer Therapy)

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Pharmaceuticals, Volume 8, Issue 1 (March 2015) – 7 articles , Pages 1-150

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